Genetic analysis confirms a link between gastrointestinal disorders and endometriosis
Authors: Philippa T.K. Saunders, Andrew W. Horne
Journal: Cell Reports Medicine (2023)

Patients with endometriosis often report gastrointestinal symptoms in addition to those usually considered hallmarks of the disorder (pain and infertility). Yang et al.1Yang F. Wu Y. Hockey R. Doust J. Mishra G.D. Montgomery G.W. Mortlock S. International Endometriosis Genetics ConsortiumEvidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management.Cell Rep. Med. 2023; 4101250https://doi.org/10.1016/j.xcrm.2023.101250Abstract Full Text Full Text PDF Scopus (0) Google Scholar identify genetic risk factors that can contribute to a shared disease etiology, providing new opportunities for improvements in disease management. Patients with endometriosis often report gastrointestinal symptoms in addition to those usually considered hallmarks of the disorder (pain and infertility). Yang et al.1Yang F. Wu Y. Hockey R. Doust J. Mishra G.D. Montgomery G.W. Mortlock S. International Endometriosis Genetics ConsortiumEvidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management.Cell Rep. Med. 2023; 4101250https://doi.org/10.1016/j.xcrm.2023.101250Abstract Full Text Full Text PDF Scopus (0) Google Scholar identify genetic risk factors that can contribute to a shared disease etiology, providing new opportunities for improvements in disease management. Endometriosis is a gynecological disorder with a definitive diagnosis based on the presence of "lesions" (tissue fragments resembling the endometrial lining of the uterus).2Saunders P.T.K. Horne A.W. Endometriosis: Etiology, pathobiology, and therapeutic prospects.Cell. 2021; 184: 2807-2824https://doi.org/10.1016/j.cell.2021.04.041Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar Patients typically report a diverse range of symptoms including pain at time of menstruation, chronic pelvic pain, abdominal bloating, and pain with defecation. The fact that some of these symptoms are the same as those associated with gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) and irritable bowel disease (IBD), can lead to delays in diagnosis and difficulties designing effective clinical management plans. Studies in Australia were the first to report evidence that the risk of developing endometriosis could be associated with specific genetic subtypes.3Saha R. Pettersson H.J. Svedberg P. Olovsson M. Bergqvist A. Marions L. Tornvall P. Kuja-Halkola R. Heritability of endometriosis.Fertil. Steril. 2015; 104: 947-952https://doi.org/10.1016/j.fertnstert.2015.06.035Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar More recently, the application of methods to identify single-nucleotide polymorphisms (SNPs) in genome-wide association studies (GWASs) using data from hundreds of thousands of individuals with diagnosed endometriosis, which were compared to age-/ethnic-matched controls, has identified SNPs that appear overrepresented in patients.4Sapkota Y. Steinthorsdottir V. Morris A.P. Fassbender A. Rahmioglu N. De Vivo I. Buring J.E. Zhang F. Edwards T.L. Jones S. et al.Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.Nat. Commun. 2017; 815539https://doi.org/10.1038/ncomms15539Crossref Scopus (208) Google Scholar That the GWASs are providing insights into mechanisms that may contribute to the etiology of endometriosis has been backed up by the apparent association of SNPs with signaling pathways involving steroid hormones and inflammatory responses, both of which have been validated in cell, tissue, and animal model studies.4Sapkota Y. Steinthorsdottir V. Morris A.P. Fassbender A. Rahmioglu N. De Vivo I. Buring J.E. Zhang F. Edwards T.L. Jones S. et al.Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.Nat. Commun. 2017; 815539https://doi.org/10.1038/ncomms15539Crossref Scopus (208) Google Scholar In this issue of Cell Reports Medicine, Yang et al. further add to our understanding of the genetic causes of endometriosis and its associated symptoms with new information that provides evidence that endometriosis shares genetic risk factors with several common GI disorders.1Yang F. Wu Y. Hockey R. Doust J. Mishra G.D. Montgomery G.W. Mortlock S. International Endometriosis Genetics ConsortiumEvidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management.Cell Rep. Med. 2023; 4101250https://doi.org/10.1016/j.xcrm.2023.101250Abstract Full Text Full Text PDF Scopus (0) Google Scholar The results extend those of a genetic analysis of shared risk factors between depression and endometriosis, where "abnormality of the gastric mucosa" showed a statistical enrichment.5Adewuyi E.O. Mehta D. Sapkota Y. Auta A. Yoshihara K. Nyegaard M. Griffiths L.R. Montgomery G.W. et al.International Endogene Consortium23andMe Research TeamGenetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality.Hum. Genet. 2021; 140: 529-552https://doi.org/10.1007/s00439-020-02223-6 (2021Crossref PubMed Scopus (0) Google Scholar Importantly, the study by Yang et al. goes beyond the usual GWAS analysis by application of Mendelian randomization with insights on the rates of co-morbidity based on data held in the UK Biobank backed up by medication usage in the UK and Australia. The UK Biobank was launched in 2006 as a project designed to provide longitudinal data from 500,000 individuals recruited between the ages of 40 and 69. To conduct analysis of the rates of co-morbidity between endometriosis and GI disorders, the numbers of women with self-reported or diagnosed endometriosis were compared to those diagnosed with each of the common GI disorders: IBS, IBD, GORD (gastro-esophageal reflux disease), PUD (peptic ulcer disease), and combined GORD/PUD (GPM). In this dataset, there were 5,392 cases of endometriosis (adenomyosis excluded) with larger numbers of women with IBS (16,330) and GORD (22,383). They used this dataset to answer two complementary questions: were women with endometriosis more/less likely to have a diagnosis of one or more of the GI disorders, and were women with any of these five disorders more/less likely to have endometriosis? The results showed clear evidence of co-morbidity: women with endometriosis were 2× as likely to suffer from IBS and 1.4× more likely to be diagnosed with GORD than those not recorded as having endometriosis. The reciprocal finding was also true—women with IBS were 2× more likely to have a diagnosis of endometriosis. The results for PUB and IBD were not as strong, and this was also the case when genetic correlations were examined. To follow up on these epidemiological findings, the authors turned to large GWAS datasets exploring shared genetic correlations complemented by Mendelian randomization to provide an estimate of causal relationships. The GWAS analysis backed up the findings from the UK Biobank with significant genetic correlations between IBS, GORD, and the combined GPM (GORD/PUD) subtype but, interestingly, no positive correlation between endometriosis and IBD was found. IBS and GPM have previously been reported to be genetically correlated, so to avoid this influencing their results they conducted extra tests on the data. A criticism of GWAS analyses is that the identification/location of disease-associated SNPs needs to be complemented by additional evidence before inferences on their impact on disease etiology/severity can be drawn. A strength of this study is the different approaches the authors have taken to increase the power of genes/pathways identified using their genetic toolkit by searching databases containing medication usage and complementing this with searching databases of drugs that might target the products of genes identified in potential pathways shared by endometriosis and GI disorders. Some genes identified by the combined GWAS/cross-trait meta-analysis and co-localization approach had previously been identified in endometriosis but not IBS or other GI disorders. Several of these are associated with the well-established role(s) of estrogen and inflammatory processes,2Saunders P.T.K. Horne A.W. Endometriosis: Etiology, pathobiology, and therapeutic prospects.Cell. 2021; 184: 2807-2824https://doi.org/10.1016/j.cell.2021.04.041Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar including RERG.6Monsivais D. Dyson M.T. Yin P. Coon J.S. Navarro A. Feng G. Malpani S.S. Ono M. Ercan C.M. Wei J.J. et al.ERbeta- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis.Mol. Endocrinol. 2014; 28: 1304-1315https://doi.org/10.1210/me.2013-1421Crossref PubMed Scopus (52) Google Scholar Data from the UK Biobank also found evidence of parallels with endometriosis with significantly higher use of hormone therapies among women with IBS, GORD, and PUD but not IBD, consistent with the co-morbidity findings. Other notable novel findings included four regions shared by endometriosis and IBS/GPM (SEMA3F, RAB5B, CCKBR [cholecystokinin type 2 receptor], and PDE4B [phosphodiesterase-4]) previously identified by GWASs as linked to GI disorders but not formally linked to endometriosis. The translational potential of the approaches described in this study is backed up by the identification of drugs designed to target the proteins encoded by CCKBR and PDE4B. CCKBR drugs are already being used for treatment of PUD and GORD and are considered an attractive therapeutic opportunity for management of chronic pain—something clearly pertinent to patients with endometriosis.7Bernard A. Danigo A. Bourthoumieu S. Mroué M. Desmoulière A. Sturtz F. Rovini A. Demiot C. The Cholecystokinin Type 2 Receptor, a Pharmacological Target for Pain Management.Pharmaceuticals. 2021; 141185https://doi.org/10.3390/ph14111185Crossref Scopus (4) Google Scholar PDE4 is considered a promising target for modulating immune cell function, and a number of drugs targeting the activity of the protein have been developed and tested in clinical trials for respiratory, skin, and neurological disorders.8Crocetti L. Floresta G. Cilibrizzi A. Giovannoni M.P. An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022.Molecules. 2022; 274964https://doi.org/10.3390/molecules27154964Crossref Scopus (21) Google Scholar To date, clinical trials suggest that their use as treatment for symptoms of IBS is promising, but a review of 5 trials involving women with endometriosis concluded that there was still insufficient evidence with respect to fertility and pain outcomes.9Grammatis A.L. Georgiou E.X. Becker C.M. Pentoxifylline for the treatment of endometriosis-associated pain and infertility.Cochrane Database Syst. Rev. 2021; 8: CD007677https://doi.org/10.1002/14651858.CD007677.pub4Crossref PubMed Scopus (10) Google Scholar In conclusion, the new insights in this study will be of interest to anyone seeking better ways to improve diagnosis and treatment of the distressing symptoms associated with both endometriosis and GI disorders. They are complemented by the evidence of a link between the gut microbiome/metabolites and the pain experience in women (the so-called "gut-brain axis"10Caputi V. Bastiaanssen T.F.S. Peterson V. Sajjad J. Murphy A. Stanton C. McNamara B. Shorten G.D. Cryan J.F. O'Mahony S.M. Sex, pain, and the microbiome: The relationship between baseline gut microbiota composition, gender and somatic pain in healthy individuals.Brain Behav. Immun. 2022; 104: 191-204https://doi.org/10.1016/j.bbi.2022.06.002Crossref PubMed Scopus (4) Google Scholar) and confirm endometriosis patient experience that has highlighted IBS-like symptoms. The authors declare no competing interests. Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease managementYang et al.Cell Reports MedicineOctober 31, 2023In BriefYang et al. provide multiple levels of evidence supporting shared etiological factors between endometriosis and gastrointestinal disorders and highlight target genes and pathways contributing to the shared etiology. The results suggest potential targets for treatment, considerations for disease management, and caution around drug contraindications for both diseases. Full-Text PDF Open Access